Abstract. Moderate and severe TBI can cause significant neuronal death and dysfunction, resulting in cognitive disability. The best strategy to restore neurologic function in TBI patients is to preserve existing neurons and to stimulate neurogenesis to replace lost neural tissue. Many therapeutics have sought to accomplish these goals, but none have succeeded, resulting in a lack of FDA-approved treatments for the restoration of cognitive disabilities that result from TBI. The exact cause of failure is not known, but we do know that brain injury induces secondary cascades that elevate levels of a transcriptional repressor of neural genes known as REST. Upregulation of REST in mature neurons prevents them from functioning properly and eventually ends in their death and increased levels of REST in stem cells and neural progenitor cells prevent them from becoming new neurons or oligodendrocytes. Previous therapeutic strategies as well as current approaches all work upstream of REST and do not account for this transcriptional block. To address this challenge, we have developed a lead biologic that promotes REST degradation and clears the injury induced transcriptional repression of neuronal genes. To engineer this lead biologic into a drug candidate for an Investigational New Drug (IND) application with the FDA we will carry out the following objectives: I. Optimize the activity, tissue targeting and intracellular transport of our drug candidate. II. Assess in vitro efficacy in human induced pluripotent stem (iPS) cells. III. Assess in vivo efficacy using a rodent model of TBI. To accomplish these objectives, Alcamena Stem Cell Therapeutics is collaborating with field leading academic scientists at Johns Hopkins University (JHU), and the Uniformed Services University of the Health Sciences (USHS/DoD). Cumulatively, these studies will inform us on the degree to which our drug candidate improves neuron and oligodendrocyte regeneration, survival and cognitive function. Additionally, the use of both human induced pluripotent stem cells and an in vivo rodent model of brain injury ensure that our results are translatable towards our long-term goal of addressing the unmet therapeutic needs of TBI patients.